Functional interactions between P-glycoprotein and CYP3A in drug metabolism.
Functional interactions between P-glycoprotein and CYP3A in drug metabolism.
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DOI：
10.1517/17425255.1.4.641
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发表时间：
2005-12-01
影响因子：
4.3
通讯作者：
Haschke, Manuel
中科院分区：
文献类型：
--
作者：
Christians, Uwe;Schmitz, Volker;Haschke, Manuel
药物代谢酶和主动转运蛋白之间的相互作用是药代动力学中的一个新兴概念。在肠粘膜中，P-糖蛋白和细胞色素P450（CYP）3A以三种方式功能性地相互作用：i）药物被P-糖蛋白反复摄取并泵出肠细胞，从而增加药物被代谢的可能性; ii）P-糖蛋白使细胞内药物浓度保持在CYP 3A代谢能力的线性范围内;和iii）P-糖蛋白将粘膜中形成的药物代谢物转运回肠腔。与肠粘膜相比，在肝细胞中，CYP 3A和P-糖蛋白的空间序列被逆转，当其中一个或两个的活性改变时，产生不同的影响。CYP 3A和P-糖蛋白均受核受体如PXR调节。CYP 3A、P-糖蛋白和PXR存在显著的遗传变异性，其表达和活性取决于联合给药的药物、草药、食物、年龄、激素状态和疾病。未来的药物基因组学和药代动力学研究必须考虑所有三个组成部分，才能得出有效的结论。
The interaction between drug-metabolising enzymes and active transporters is an emerging concept in pharmacokinetics. In the gut mucosa, P-glycoprotein and cytochrome P450 (CYP)3A functionally interact in three ways: i) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, thus increasing the probability of drugs being metabolised; ii) P-glycoprotein keeps intracellular drug concentrations within the linear range of the metabolising capacity of CYP3A; and iii) P-glycoprotein transports drug metabolites formed in the mucosa back into the gut lumen. In comparison with the gut mucosa, in hepatocytes the spatial sequence of CYP3A and P-glycoprotein is reversed, resulting in different effects when the activity of one or both are changed. CYP3A and P-glycoprotein are both regulated by nuclear receptors such as the pregnane X receptor (PXR). There is significant genetic variability of CYP3A, P-glycoprotein and PXR and their expression and activity is dependent on coadministered drugs, herbs, food, age, hormonal status and disease. Future pharmacogenomic and pharmacokinetic studies will have to take all three components into account to allow for valid conclusions.